By Marc Greilsamer
When the FDA approved the use of <"http://www.yourlawyer.com/topics/overview/drug_coated_stents">drug-coated stents on April 24, 2003, it was hailed as a landmark advance in the treatment of blocked arteries.
Ã¢â‚¬Å“Drug-coated stents will be the new standard of cardiovascular care essentially immediately upon their release,Ã¢â‚¬Â Dr. Campbell Rogers, director of the Cardiac Catheterization Laboratory at Brigham and Women’s Hospital (BWH), said at the time. House and Human Services Secretary Tommy Thompson called the decision Ã¢â‚¬Å“a significant step forward in the treatment of heart diseaseÃ¢â‚¬Â while Mark McClellan, FDA Commissioner during that period, added that Ã¢â‚¬Å“drug-eluting stents combine drugs with medical devices to provide more effective care for many patients with heart disease. FDA is working to make sure its regulatory procedures encourage the quick and efficient approval of such safe and effective combination products.Ã¢â‚¬Â
Significantly, the FDAÃ¢â‚¬â„¢s announcement also made the following claim: Ã¢â‚¬Å“The types of adverse events seen with the drug-eluting stent were similar to those that occurred with the uncoated stent.Ã¢â‚¬Â However, only three and a half years later, that statement is being challenged by a growing number of medical professionals, researchers, and consumer watchdogs who fear that the drug-coated device brings with it a higher risk of blood clots that can lead to heart attacks and strokes. Today, the questionable safety of drug-coated stents threatens to shake up this multibillion-dollar industry, raising a myriad of medical and legal issues.
On December 7 and 8, the FDA held a public Circulatory System Devices Advisory Panel meeting to discuss the issue and delivered the kind of mixed message that is typical at the FDA: Drug-coated stents were deemed safe for a certain subset of the patient population, but were also associated with a higher risk of blood clots, heart attacks, and death in the majority of patients. The panel recommended that the FDA issue new warnings for doctors and patients to reflect the elevated risk. The panel also sought to reduce instances of Ã¢â‚¬Å“off-labelÃ¢â‚¬Â usage, which accounts for more than half of the drug-coated stent market. Yet they saw no compelling reason to pull the controversial devices off the market.
In the long run, however, this may not be good news for stent makers. Ã¢â‚¬Å“Increased incidents of injury and adverse events are always important factors to examine when assessing the liability case against the manufacturers of drugs or medical devices,Ã¢â‚¬Â says Jason Mark, an attorney at Parker & Waichman LLP who runs the firmÃ¢â‚¬â„¢s mass tort unit. Ã¢â‚¬Å“With safer alternative designs available to patients that pose less thrombotic risk, manufacturers who place these products into the stream of commerce do so at their own peril and, unfortunately, at the peril of unsuspecting patients.Ã¢â‚¬Â
In 2003, the news was all good for Cordis Corporation, the division of Johnson & Johnson that developed the drug-eluting stent (DES). At the time, the only stents in use were bare-metal stents (BMS). These devices–a kind of wire-mesh scaffolding–were used to prop open clogged arteries after angioplasty and had met with much success. However, according to the FDA, roughly 15 to 30 percent of stent patients suffered from restenosis (re-clogging of the artery) within a year of the procedure and had to be treated again with another angioplasty or bypass surgery.
The drug-eluting stent was developed to solve the problem of restenosis. By releasing a drug to retard cell growth and stop scar tissue from forming within arteries that have been opened, the new device was designed to prevent the arteries from becoming blocked again. Cordis had funded a national clinical trial to test the deviceÃ¢â‚¬â„¢s effectiveness, and it was lauded as highly successful. The combined occurrence of repeat angioplasty, bypass surgery, heart attacks, and death was 8.8 percent for drug-eluting stent patients and 21 percent for the uncoated stent patients. The FDA said the new device was found to Ã¢â‚¬Å“significantly reduce the rate of re-blockage that occurs with existing stents.Ã¢â‚¬Â BWHÃ¢â‚¬â„¢s Dr. Rogers, who had been involved in the New England-based part of the trial, noted, Ã¢â‚¬Å“When we tested the drug-coated devices versus the plain metal version on patients, the results were very compelling. In approximately 95 percent of patients receiving the drug-coated stents, restenosis was prevented.Ã¢â‚¬Â
Patients and medical professionals were so excited about the drug-coated stent that angioplasty procedures were being delayed specifically to await the FDAÃ¢â‚¬â„¢s approval of the Cypher, CordisÃ¢â‚¬â„¢ revolutionary Sirolimus-Eluting Coronary Stent. The FDA issued its blessing in April of 2003, and by June, the device was already in short supply as demand soared. Patients had heard the news about drug-eluting stents, and suddenly, nobody wanted a bare-metal stent anymore.
It didnÃ¢â‚¬â„¢t take long for the mood to change. In early July of 2003, less than three months after it approved the Cypher stent, the FDA issued its first warning about the product. In a July 8 alert, the agency stated: Ã¢â‚¬Å“Since the productÃ¢â‚¬â„¢s introduction it is estimated that over 50,000 patients have received a Cypher stent. To date, FDA has received 47 Medical Device Reports (MDRs) of stent thrombosis occurring at the time of implantation or within a few days of implantation.Ã¢â‚¬Â
Cordis sent a letter to healthcare professionals that week, notifying them of the incidence of thrombosis and reminding them of four important considerations with regard to using the Cypher: selection of the appropriate stent size; selection of appropriate patients for implantation; use of an adequate antiplatelet regimen to reduce the risk of clot formation; and the use of the proper technique for stent deployment. The third recommendation–the one related to blood clotting–would become a key element in the implantation and maintenance of drug-coated stents.
The news only got worse. On October 29, 2003, the FDA felt compelled to issue a second warning about the new device. The agency had by then received nearly 300 reports of adverse effects, 60 of which resulted in fatalities. In addition, there had been 50 reports of hypersensitivity and allergic reactions including pain, rash, respiratory alterations, hives, itching, fever, and blood pressure changes; several of these events proved fatal as well. Only a month later, the FDA provided updated numbers. TheyÃ¢â‚¬â„¢d received 75 new reports of thrombosis and 20 new incidents of hypersensitivity. Meanwhile, Cordis had distributed nearly 600,000 Cypher stents by that point, pumping them out at well more than 100,000 a month.
Doctors and patients proceeded with little caution over the next year, putting aside fears of thrombosis and other complications, and the popularity of the drug-eluting stent continued to grow. After gaining FDA approval in March of 2004, Boston Scientific introduced its own drug-coated stent, the Taxus, coated with paclitaxel. On October 18, 2004, a year after it issued its second DES warning, the FDA announced its conclusion that there was virtually no difference in the thrombosis risks of drug-eluting stents when compared to bare-metal stents.
Ã¢â‚¬Å“The Cypher stent,Ã¢â‚¬Â said the agency, Ã¢â‚¬Å“when implanted in accordance with the approved indications for use, is not associated with an excess of SATs [sub-acute thromboses] compared to bare-metal stents. SAT remains a relatively rare event that occurs within the first 30 days following the stenting procedure.Ã¢â‚¬Â
While the safety of the DES may still have been questioned, the efficacy of the product was almost universally accepted: Drug-coated stents were instrumental in reducing the need for second surgical procedures. By the end of 2005, more than 90 percent of all stents being implanted in heart patients were drug-eluting stents.
Medical professionals were so thrilled that drug-coated stents reduced the risk of restenosis, they were perhaps willing to overlook the fact that the risk of stent thrombosis may have been growing. Several studies released in 2006 have brought the safety concerns back to the forefront of the discussion.
The first significant study was the BASKET-LATE (Basel Stent Kosten EffektivitÃƒÂ¤ts Trial-Late Thrombotic Events) trial, which was set up to assess rates of cardiac death and myocardial infarction (MI) in stent patients who stopped using clopidogrel, the anti-clotting drug sold under the brand name Plavix. The randomized observational study fitted 499 patients with a DES and 244 with a BMS. According to the study results, in the year after clopidogrel discontinuation, patients with drug-eluting stents were twice as likely to suffer late stent thrombosis as those with bare-metal stents. Researchers also concluded that the risk of cardiac death or MI with the use of drug-eluting stents was Ã¢â‚¬Å“significantly higherÃ¢â‚¬Â than the risk with the use of bare-metal stents: 4.9 percent versus 1.3 percent in the year after clopidogrel discontinuation.
Dr. Matthias E. Pfisterer created quite a stir when he first presented these results in March of 2006 at the Annual Scientific Session of the American College of Cardiology in Atlanta, and since that point, the debate has only gotten more heated. In September, the issue commanded center stage at the European Society of Cardiology/World Congress of Cardiology meeting in Barcelona, Spain, when three separate European studies questioned the long-term safety of drug-eluting stents.
The major presentation was made by Dr. Edoardo Camenzind of the University Hospital in Geneva. Dr. Camenzind conducted a meta-analysis of nine clinical trials and more than 5,000 patients to determine the risks of the DES versus the BMS. Camenzind found that the incidence of death or heart attack was higher for DES patients than for BMS patients–and higher for Cypher patients than for Taxus patients. Cypher patients were as much as 30 to 40 percent more likely to suffer serious adverse events than those with bare-metal stents while Taxus elevated the risks roughly 5 to 10 percent.
A second meta-analysis came from Dr. Alain J. Nordmann of the University Hospital in Basel. In this study, researchers examined 17 randomized trials and found that the Cypher was associated with significantly higher rates of noncardiac death when compared to bare-metal stents. The ThoraxCenter of Rotterdam presented its own study, which tracked stent thrombosis rates in more than 8,000 patients. Dr. Peter Wenaweser reported the cumulative rate of thrombosis was 2.9 percent, not terribly significant, but the troubling news was that the risk of thrombosis did not seem to lessen over time. Instead, the risk associated with DES patients continued to increase at the same rate (roughly 0.6 percent) year by year.
The biggest bomb at the September conference in Barcelona was dropped by Boston Scientific itself. The stent manufacturer announced that its own internal research had found a slightly higher, statistically noteworthy risk of blood clotting in patients who received their Taxus drug-eluting stents when compared to those whoÃ¢â‚¬â„¢d been implanted with bare-metal stents. Their review looked at 3,500 patients and included four yearsÃ¢â‚¬â„¢ worth of data to determine the risks of late stent thrombosis (blood clotting in the stent area from the period beginning six months after implantation). Their admission was the first of its kind by any of the stent makers.
Immediately following the Barcelona meetings, the FDA decided to issue a new statement regarding drug-eluting stents. Ã¢â‚¬Å“We are aware of recent data suggesting a small but significant increase in the rate of death and myocardial infarction (heart attack) possibly due to stent thrombosis (a blood clot in the stent) in patients treated with DES,Ã¢â‚¬Â the agency said, specifically citing the BASKET-LATE trial and Dr. CamenzindÃ¢â‚¬â„¢s meta-analysis. Ã¢â‚¬Å“The small but significant increase in the rate of death and myocardial infarction observed in these studies was noted in patients followed 18 months to 3 years after stent implantation.Ã¢â‚¬Â
The agency stressed the need for further studies and noted the importance of effective Plavix regimens to prevent clotting in DES patients. They also announced DecemberÃ¢â‚¬â„¢s public meeting of the Circulatory System Devices Advisory Panel to discuss the issues in greater detail. But ultimately, the agency was quite clear when it said: Ã¢â‚¬Å“At this time, FDA believes that coronary drug-eluting stents remain safe and effective when used for the FDA-approved indications. These devices have significantly reduced the need for a second surgery to treat restenosis for thousands of patients each year.Ã¢â‚¬Â
The issue gained momentum in October at the Transcatheter Cardiovascular Therapeutics (TCT) meeting in Washington, D.C. A highly anticipated presentation by Drs. Gregg W. Stone and Marty Leon further clouded the medical issues at hand. Yes, they said, drug-eluting stents were indeed associated with significantly higher rates of late stent thrombosis. Yet, notably, they also claimed that the mortality rates among DES patients were no higher than those of BMS patients. That was largely because BMS patients were more than twice as likely to suffer re-clogging of their arteries.
With the debate raging on and contradictory evidence mounting, the stage was set for the FDAÃ¢â‚¬â„¢s public meeting in December. The fate of the $6 billion DES industry largely hung in the balance.
The FDAÃ¢â‚¬â„¢s public meeting of the Circulatory System Devices Advisory Panel on December 8 and 9 was not without its own share of controversy.
For one thing, the FDA decided to use physicians with a monetary stake in the products they were reviewing on behalf of the agency. Six doctors on the advisory panel had financial links to stent makers Johnson & Johnson and Boston Scientific; the FDA granted conflict-of-interest waivers to all six of the physicians in question.
Ã¢â‚¬Å“The reality is that the FDA sees industry as its client,Ã¢â‚¬Â notes Jason Mark, the Parker & Waichman attorney. Ã¢â‚¬Å“The interests of the FDA are too often aligned with the interests of industry, and itÃ¢â‚¬â„¢s the patients who time and time again suffer the consequences.Ã¢â‚¬Â
Considering who was chosen for the panel, perhaps itÃ¢â‚¬â„¢s not surprising that the group recommended, for the most part, a wait-and-see, business-as-usual approach. The panel did recommend new label warnings highlighting the increase in the risk of sudden heart attack or death in DES patients. Yet, in its own inimitable way, the FDA managed only to complicate matters by adding fuel to both sides of the DES argument.
While some physicians feel the devices may be too risky for the marketplace, others feel that the new warnings may discourage potential DES recipients who would truly benefit. Meanwhile, new studies continue to emerge with regard to the increased risk of thrombosis in DES patients; a recent Cleveland Clinic review assessed the risk of thrombosis in DES patients as being four to five times greater than that of BMS patients.
With millions and millions of patients already having received drug-coated stents–some estimates put the total number of DES patients as high as 6 million–even a very small increase in the risk of thrombosis becomes all the more significant. Writing in Cardiosource, the website of the American College of Cardiology, Drs. Sanjay Kaul and George A. Diamond noted that, based on the available evidence, drug-eluting stents may be responsible for more than 2,000 additional deaths every year when you consider the fact that roughly 1 million Americans per year receive a DES.
Ã¢â‚¬Å“Our romance with new technology–DES being only the most recent instance–is entirely understandable,Ã¢â‚¬Â Drs. Kaul and Diamond write. Ã¢â‚¬Å“Technological innovation accounts for much of the miracle in modern medicine. It is entirely understandable, then, that: 1) device companies should want to develop new technology and support clinical trials necessary for regulatory approval and marketing so as to profit from the sale of that technology in a capitalistic market; 2) medical investigators should want to perform and publish such studies as a way to advance their careers; 3) insurance companies should want to rely on this information to justify reimbursing hospitals and physicians for utilization of that technology lest they be charged with restricting access to care in return for reducing their costs; and 4) hospitals and physicians should want to employ such state-of-the-art technology, and that patients should demand its use–even before long-term outcome trials confirm the short-term promise of that technology.
Ã¢â‚¬Å“Together, all these individually understandable incentives conspire to introduce promising new technology too quickly into the medical marketplace and to encourage its rapid overutilization. It is not at all surprising, then, that conflicts should exist between clinical practice and its evidentiary support, and that many DES interventions are thereby insufficiently justified.Ã¢â‚¬Â
While those two doctors donÃ¢â‚¬â„¢t believe a recall or moratorium on DES is necessary, they do support further FDA review and the resulting labeling changes as well as Ã¢â‚¬Å“a more accurate, timely, and comprehensive post-market surveillance program.Ã¢â‚¬Â They also believe the FDA should be doing more to curtail off-label uses, which still account for more than half of DES implantation. Ã¢â‚¬Å“Although the FDA does not have the mandate to impact medical practice,Ã¢â‚¬Â they note, Ã¢â‚¬Å“it should nevertheless leverage its relationships with medical professional societies and device sponsors to collaborate on the development and implementation of new tools and programs that help mitigate unnecessary risk and promulgate best practice standards.Ã¢â‚¬Â
If nothing else, the DES debate has assured that most healthcare professionals will be more vigilant and discerning when addressing the risks and benefits of DES usage. Based on the available findings, doctors should only recommend drug-eluting stents for patients with a high risk of restenosis or those patients who cannot or will not handle long-term antiplatelet therapy. Doctors should not be afraid to employ bare-metal stents in certain cases where the DES may prove too risky. (Since bare-metal stents can be three to four times cheaper than drug-coated stents, the issue may have financial ramifications as well.)
The use of clopidogrel (Plavix) has proven to be essential to the long-term health of DES patients. However, the FDA has not yet approved the drug for that usage, meaning that DES recipients must use the drug off-label. Mostly all parties agree that extending the antiplatelet therapy in DES patients may be necessary in order to prevent dangerous blood clotting.
As with any new drug, therapy, or device, long-term side effects may take years to reveal themselves. The hope is that the increased scrutiny facing drug-eluting stents will lead to better decisions by the medical community, further research by the manufacturers, and greater understanding and awareness on the part of patients themselves.